Synaptic Connectivity between the Cortex and Claustrum Is Organized into Functional Modules

The widespread reciprocal connectivity between the claustrum and the neocortex has stimulated numerous hypotheses regarding its function; all of these suggest that the claustrum acts as a hub that connects multiple cortical regions via dense reciprocal synaptic pathways. Although the connectivity between the anterior cingulate cortex (ACC) and the claustrum has been proposed as an important pathway for top-down cognitive control, little is known about the synaptic inputs that drive claustrum cells projecting to the ACC. Here, we used multi-neuron patch clamp recordings, retrograde and anterograde viral labeling, and optogenetics in mouse claustrum to investigate cortical inputs and outputs of ACC-projecting claustrum (CLA-ACC) neurons. Both ipsilateral and contralateral cortical regions were found to provide synaptic input to CLA-ACC neurons. These cortical regions were predominantly frontal and limbic regions and not primary sensorimotor regions. We show that CLA-ACC neurons receive monosynaptic input from the insular cortex, thereby revealing a potential claustrum substrate mediating the Salience Network. In contrast, sensorimotor cortical regions preferentially targeted non CLA-ACC claustrum neurons. Using dual retrograde labeling of claustrum projection neurons, we show selectivity also in the cortical targets of CLA-ACC neurons: whereas CLA-ACC neurons co-projected mainly to other frontal regions, claustrum neurons projecting to primary sensorimotor cortices selectively targeted other sensorimotor regions. Our results show that both cortical inputs to and projections from CLA-ACC neurons are highly selective, suggesting an organization of cortico-claustral connectivity into functional modules that could be specialized for processing different types of information. [Display omitted] •Frontal and limbic cortical regions preferentially target CLA-ACC neurons•Sensorimotor cortical regions preferentially targeted non CLA-ACC claustrum neurons•An Insula-CLA-ACC pathway is described, which may underlie the Salience Network•CLA-ACC neurons mainly co-project to other frontal cortical regions Using a combination of electrophysiology and anatomical tracing, Chia et al. show that both cortical inputs to and projections from CLA-ACC neurons are highly selective, suggesting that cortico-claustral connectivity is organized as functional modules, specialized in processing different types of information.